Members of this Center have demonstrated that chronic alcohol ingestion renders humans and experimental animals susceptible to acute lung injury. This novel observation has provided an unprecedented opportunity to explore the mechanisms that lead to acute lung injury, and the molecules involved this process. We have found that one way in which ethanol affects the lung is by activating lung tissue remodeling resulting in the increased expression of pro-fibrotic growth factors, matrix-degrading proteases, and extracellular matrix molecules like fibronectin. These findings suggest that chronic alcohol ingestion results in alterations in lung matrix content and composition. The observation that alcohol induces fibronectin expression is important because this matrix glycoprotein is highly expressed in all forms of clinical and experimentally-induced lung injury, and has been implicated in the pathobiology of this illness. While investigating the mechanisms responsible for these effects, we found that ethanol was able to stimulate fibronectin gene transcription and protein production in lung fibroblasts. This effect appeared dependent on the activation of Mitogen-Activated Protein Kinases and induction of the transcription factor CREB. The ethanol-induced fibronectin response was inhibited by alpha-bungarotoxin suggesting that the interaction of ethanol with lung fibroblasts is mediated, at least in part, by nicotinic acetylcholine receptors (nAChRs). Finally, we found that fibronectin induces potent transcription factors thereby priming lung cells to express exaggerate amounts of proinflammatory cytokines. Based on the above, we hypothesize that ethanol induces fibronectin expression in the lung by acting on nicotinic acetylcholine receptors (nAChRs) that trigger signaling and transcriptional events that stimulate transcription of the fibronectin gene. Furthermore, we hypothesize that increased deposition of fibronectin in the lung is one factor that contributes to the ethanol-induced susceptibility to acute lung injury by priming fibronectin-responsive cells to injurious stimuli. This hypothesis will be tested in aims designed to: 1) Determine the role of nAChRs in ethanol-induced fibronectin expression, 2) Determine the intracellular pathways that mediate the response, 3) Elucidate the effects of ethanol-induced fibronectin on transcription factor induction and cytokine expression in lung cells, and 4) Study the role of alpha7 nAChRs and fibronectin in vivo using a murine model of ethanol-related lung injury.